对硝基苯酚 (2) 与 4-(2- 氯乙基 ) 吗啉盐酸盐 (3) 发生亲核取代反应得到 4-[2-(4- 硝基苯氧基 ) 乙基 ] 吗啉 (4)， 4 经 10％钯炭氢化还原得到 4-[2-(4- 吗啉基 ) 乙氧基 ] 苯胺 (5)。5 经 2 步环化反应得到 7-[2-(4- 吗啉基 ) 乙氧基 ]-2-(4- 硝基苯基 )咪唑并 [2,1-b][1,3]苯并噻唑 (8)。8经铁粉和氯化铵还原得到4-[7-[2-(4-吗啉基 )乙氧基 ]咪唑并 [2,1-b][1,3]- 苯并噻唑 -2- 基 ] 苯胺 (9)。另以 3- 氨基 -5- 叔丁基异 唑 (10) 和氯甲酸苯酯反应得苯基 (5- 叔丁基异 唑 -3- 基 ) 氨基甲酸酯 (11)。用 9 与 11 反应得到奎扎替尼 (1)，终产物纯度为 99.17％，总收率为 55％(以 2 计 )。该方法所使用起始原料 2 价廉易得，且 3 的用量大大降低，反应条件相对温和，后处理操作简便，可为工业化生产提供参考。
Abstract
4-Nitrophenol(2) reacted with 4-(2-chloroethyl)morpholine hydrochloride(3) to obtain 4-[2-(4-nitrophenoxy)ethyl]morpholine(4) through nucleophilic substitution. 4-[2-(4-Morpholinyl)ethoxy]aniline(5) was obtained by hydrogenation of compound 4 with 10％Pd/C, which was used to prepare the 7-[2-(4-morpholinyl)- ethoxy]-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole(8) via two steps of cyclization. 4-[7-[2-(4-Morpholinyl)- ethoxy]-imidazo[2,1-b][1,3]benzothiazole-2-yl]aniline(9) was prepared from the compound 8 by reduction of the nitro group with iron and ammonium chloride. Phenyl-[5-(t-butyl)isoxazol-3-yl]carbamate(11) was synthesized from 3-amino-5-t-butyl-isoxazole(10) by treatment with phenyl chloroformate. Compound 9 reacted with compound 11 to give quizartinib(1) in a purity of 99.17%, and the total yield was 55％(based on 2). In this reported route, starting material was inexpensive and easy to obtain, and the amount of 3 was greatly reduced. This method had mild reaction conditions and simple work-up, and it could provide reference for industrial production.
关键词
急性髓系白血病 /
FLT3 抑制剂 /
奎扎替尼 /
合成
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Key words
acute myelogenous leukemia(AML) /
FLT3 inhibitor /
quizartinib /
synthesis
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参考文献
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